1. Field of the Invention
The present invention relates to pharmacogenetics and cardiology. More specifically, the present invention relates, in part, to methods of predicting the efficacy of β-adrenergic receptor targeting agent treatment in a patient with a cardiovascular condition based on the patient's genotype of certain polymorphisms in endothelin gene system members.
2. Description of Related Art
According to the American Heart Association (AHA), about 79 million Americans have some form of cardiovascular disease, which can include high blood pressure, coronary heart disease (heart attack and chest pain), cardiomyopathy, stroke, birth defects of the heart and blood vessels, and congestive heart failure, and close to a million die from such conditions every year. The annual report of the AHA further states that cardiovascular disease kills more Americans than the next seven causes of death combined, including cancer. Heart disease accounted for 40% of all deaths in the U.S. in 1999, and mortality from heart failure is approximately 50% within 5 years.
In the United States alone there are approximately six million people, about 1.5% of the population, with chronic heart failure (“HF”), and roughly 550,000 new patients are diagnosed each year. Medical therapy has made progress in treating HF, but morbidity and mortality remain high (Mann et al., 2005). The current standard of care in HF involves the use of inhibitors (ACE inhibitors, ARBs, and/or aldosterone receptor antagonists) of the renin-angiotensin-aldosterone system (RAAS), and β-blockers, which competitively inhibit β-adrenergic receptors on cardiac myocytes. β-blocker therapy is standard treatment for systolic heart failure and reduces allcause mortality by 34-65% (CIBIS-II Investigators, 1999; Packer et al., 1996; Packer et al., 2001). These data are in agreement with other large drug trials where only between 25-60% of patients benefit from exposure to medication as compared to placebo (Wilkinson, 2005; Evans and Relling, 2004; Weinshilboum, 2003).
Even though most β-blocker trials in heart failure have shown group beneficial effects, there is substantial interindividual variability in outcome that is not explained by baseline clinical characteristics (CIBIS-II Investigators, 1999). Interindividual variability in the response to pharmacologic therapy is recognized with virtually all drugs. In circumstances such as the treatment of chronic heart failure with β-blockers—where morbidity and mortality are high, the titration algorithm is complex, the interindividual variability is substantial, and additional treatment options exist—assessing the likelihood of a favorable (or adverse) long-term response to drug therapy can have a significant impact on decision making.
Another cardiovascular disease, cardiomyopathy, is a disease of the heart muscle. This form of cardiovascular disease is often distinctive, both in general symptoms and in patterns of blood flow, thus facilitating diagnosis. Increasing recognition of this disease, along with improved diagnostic techniques, have shown that cardiomyopathy is a major cause of morbidity and mortality. In some areas of the world it may account for as many as 30% of all deaths due to heart disease.
Several types of cardiomyopathy are known, including ischemic, dilated, hypertrophic, restrictive and idiopathic (and combinations thereof). The prognosis for all types of these diseases is often poor. For example, the survival rate of dilated cardiomyopathy for five years is typically 50 to 60%. Treatment of cardiomyopathy involves restricted activity, stress avoidance, treatment with β-blockers, prophylactic antibiotic therapy, use of anti-coagulants, calcium channel blockers, surgery and cardiac transplantation. With this variety of treatments available, it would be helpful to identify which patients would benefit the most from one treatment as compared to another. For example, dobutamine stress cardiovascular magnetic resonance has been employed to predict whether or not β-blocker treatment of patients exhibiting severe ischemic cardiomyopathy will be beneficial (Kaandorp 2005). However, the small number of patients tested limits the significance and clinical applicability of these findings. Other means of predicting which patients will benefit from β-blocker treatment are also needed.